T 1149/09 (Vaccinia virus formulation/BAVARIAN NORDIC) 24-10-2013

Admissibility of the appeal of opponent 02

1. As no written statement setting out the grounds of appeal has been filed, the appeal of opponent 02 is rejected as inadmissible (Article 108 EPC, third sentence, in conjunction with Rule 101(1) EPC). It could not therefore maintain its request that the decision under appeal be set aside and the patent be revoked but as an "other party" only request that the appeal of appellant I be dismissed. In the event, opponent 02 took no part in the appeal proceedings after filing its notice of appeal.

Admissibility of the appeals of the proprietor (appellant I) and of opponent 01 (appellant II)

2. These appeals are admissible.

Main request (claims as granted) - claim 1

Priority

3. In the decision under appeal the opposition division decided that the claimed subject-matter was not entitled to the claimed priority. Appellant I has contested this decision.

4. Claim 1 relates to a formulation comprising a vaccinia virus having a titer of at least 10**(6) TCID50 per mg total protein. Appellant I relied on page 10, lines 8 to 10 and page 11, lines 19 to 20 of the previous application as providing priority for the feature "at least

10**(6) TCID50 per mg total protein".

5. The previous application discloses on page 10,

lines 8 to 10 that "Especially for vaccination of human beings it is thus preferred that the virus is further purified before it is included into a formulation according to the present invention". In the board's judgement, the mere indication that the virus is further purified does not directly and unambiguously disclose a minimum value of TCID50 per mg total protein, let alone a formulation comprising a vaccinia virus having a titer of at least 10**(6) TCID50 per mg total protein.

6. Page 11, lines 18 to 21 of the earlier application discloses that "The poxviruses are contained in the aqueous formulation in a concentration range of 10**(5)to 10**(9) TCID50/ml, preferably in a concentration range of 10**(6) to 5x10**(8) TCID50/ml, most preferably in a concentration range of 10**(7) to 10**(8) TCID50/ml". This disclosure relates to concentration ranges of poxviruses with defined lower and upper endpoints in aqueous formulations given in TCID50/ml. It does however not allow the deduction of any minimum value of TCID50 per mg total protein since the presence of proteins of non-viral origin is not excluded.

7. For the above reasons the feature "at least 10**(6) TCID50 per mg total protein" can not be derived directly and unambiguously from the previous application, which therefore does not relate to the same invention (see opinion G 2/98 of the Enlarged Board of Appeal, OJ 2001, 413, Headnote). Therefore the effective date of claim 1 as granted is the filing date. Accordingly, documents (D3) and (D17) belong to the state of the art pursuant to Article 54(2) EPC.

Inventive step

Closest prior art

8. The opposition division considered document (D1) to represent the closest prior art. On appeal the parties disagreed as to which document constituted the closest prior art. While appellant I considered document (D14) to represent the closest prior art, appellant II considered document (D1) to represent the closest prior art.

9. From the patent as a whole it is understood that the purpose of the present invention is the provision of a poxvirus-containing formulation for freeze-drying which leads to a stable freeze-dried product, wherein the poxvirus is preferably a purified or at least partially purified virus comprising low amounts of non-poxvirus associated proteins, and is in particular a vaccinia virus (see paragraphs [0009], [0013], [0014] of the patent in suit).

10. Document (D1) relates to preparations of viruses, e.g. for vaccines, to their stabilisation and to their use (see column 1, lines 11 to 15). Document (D1) discloses (see abstract, examples 4 to 6) stabilized dried pharmaceutical compositions dispersible in aqueous liquid which comprise - besides purified virus - sucrose, dextran, sodium glutamate, and Tris buffer. Compositions disclosed in document (D1) include compositions free from protein (other than any protein forming part of the active vaccine component). According to column 6, lines 17 to 18 of document (D1) "The invention is particularly applicable for example to herpesviruses and poxviruses among others". In the examples, the virus used is not a poxvirus but HSV-2, a herpes virus. It is undisputed that examples 4 to 6 of document (D1) disclose formulations which - except for the virus - are identical to the claimed formulations.

11. Document (D14), a review article, relates to the formulation, stability and delivery of live attenuated vaccines for human use. According to document (D14), the inherent lability of live organisms presents a particular formulation challenge in terms of stabilizing and preserving vaccine viability during manufacturing, storage and administration (see abstract). Document (D14) examines pharmaceutical approaches to the stabilization, formulation, and lyophilisation of biological macromolecules in general, as well as the specific applicability of these principles to live attenuated viral and bacterial vaccines. Finally, document (D14) discloses examples of accelerated and real-time storage stability testing of various viral preparations, including various vaccinia virus formulations, inter alia a formulation comprising the Elstree strain, 5% Na-glutamate, 1.25% sucrose and 5% peptone (see Table 3 on page 54).

12. Both documents thus relate to the stabilization of live viral vaccines and provide stable formulations comprising live viruses. While document (D1) discloses formulations which - except for the virus - are identical to the claimed formulation (see examples 4 to 6), document (D14) discloses stable formulations which comprise a vaccinia virus, but differ from the claimed formulations in their chemical composition (see Table 3).

13. According to established case law of the Boards of Appeal, when deciding which of two documents (here documents (D1) and (D14)), has to be regarded as closest prior art, it has to be considered which document the skilled person would have realistically taken as a starting point under the circumstances of the claimed invention (Case Law of the Boards of Appeal of the European Patent Office, 7th edition 2013, I.D.3.4.2). Among these "circumstances", aspects such as the subject-matter of the invention, the formulation of the original problem, the intended use and the effects to be obtained should generally be given more weight than the maximum number of identical technical features. In the present case, where the stated purpose of the invention is the provision of stable poxvirus containing formulations, in the board's judgement, the realistic starting point for the skilled person is a stable vaccinia virus formulation as disclosed in document (D14).

14. Hence, the board concludes that document (D14) not only discloses subject-matter conceived for the same purpose but is also the most promising springboard towards the invention. Therefore the board decides that document (D14) represents the closest state of the art for the purpose of the assessment of inventive step of the subject-matter of claim 1.

15. The parties also disagreed on which of the formulations disclosed in document (D14) qualified as the closest prior art. Appellant I considered the formulation comprising an Elstree strain (a vaccinia virus), 5% peptone (a pharmaceutically acceptable polymer) and 5% sorbitol disclosed in line 1 on page 54 of document (D14) to represent the closest prior art. Appellant II considered the formulation comprising an Elstree strain (a vaccinia virus), 5% Na-glutamate, 1.25 % sucrose (a disaccharide), and 5% peptone (a pharmaceutically acceptable polymer) disclosed in line 3 on page 54 of document (D14) to represent the closest prior art.

16. In the board's judgement, the formulation comprising an Elstree strain, 5% Na-glutamate, 1.25 % sucrose, and 5% peptone requires less structural modifications to arrive at the claimed invention than the formulation comprising an Elstree strain, 5% peptone, and 5% sorbitol, and is accordingly considered to represent the closest prior art. Pursuant to paragraph [0047] of the patent in suit the term "stable, poxvirus containing composition" is used to define poxvirus containing compositions in which the overall loss in virus titer at an incubation temperature of 37°C during 28 days is less than 0,5 logs. According to Table 3 of document (D14) the loss in virus titer of the formulation is 0,4 at an incubation temperature of 37°C during 4 weeks. Accordingly, this formulation is stable.

17. Appellant I's contention that the selection of this formulation is based on hindsight is not tenable, since the Boards of Appeal have established that, in circumstances such as the present, the prior art requiring the minimum of structural modifications to arrive at the claimed invention qualifies as the closest prior art (see Case Law of the Boards of Appeal of the European Patent Office, 7th edition 2013, I.D.3.1).

Technical problem and solution

18. The subject-matter of claim 1 differs from the formulation disclosed in line 3 on page 54 of document (D14) in that the virus has a titer of at least 10**(6) TCID50 per mg total protein and in the presence of the buffer. Appellant I took the view that these differences resulted in a vaccinia virus formulation that was pure enough to allow direct administration upon reconstitution while being stable enough to prevent loss of viral titer during storage and formulated the problem accordingly.

19. The first issue to be addressed is whether the effect is achieved across the scope of the claim, in other words whether the problem is plausibly solved across the scope of claim 1.

20. The board notes that claim 1 relates to a formulation defined as comprising inter alia a vaccinia virus having a titer of at least 10**(6) TCID50 per mg total protein, a disaccharide, a pharmaceutically acceptable polymer, and a buffer. Accordingly, the presence of serum, animal proteins, or peptone is not excluded. Indeed, according to the patent in suit a titer of at least 10**(6) TCID50 per mg total protein corresponds only to a partially purified virus (see paragraph [0029] of the patent in suit).

21. The patent in suit reports stabilization of Modified Vaccinia Virus Ankara (MVA) with a dilution buffer comprising dextrane, sucrose, and L-glutamic acid, termed DSG. The dilution buffer DSG was used at various defined final concentrations, wherein the TCID50/ml of the final formulation was adjusted to 5 x 10**(8) TCID50/ml with a physiological Tris-buffer (see paragraphs [0066] and [0067], Table 6). However, neither the nature nor the concentrations of any of the components of the formulation, i.e. the disaccharide, the polymer or the buffer are specified in claim 1. Therefore in the board's judgement, the results obtained in the accelerated stability test carried out in the patent in suit with six defined formulations can not be plausibly extended to all formulations falling within the scope of claim 1.

22. According to the case law of the Boards of Appeal, alleged advantages to which the patent proprietor merely refers, without offering sufficient evidence to support the comparison with the closest prior art, cannot be taken into consideration in determining the problem underlying the invention and therefore in assessing inventive step (Case Law of the Boards of Appeal of the European Patent Office, 7th edition 2013, I.D.4.4.2). The board concludes that the problem as formulated by appellant I (see point 18 above) is not plausibly solved by all formulations falling within the scope of claim 1. Accordingly, the problem has to be reformulated to a less ambitious problem which can be considered as being plausibly solved (Case Law of the Boards of Appeal of the European Patent Office, 7th edition 2013, I.D.9.8.1). In the board's judgement, accordingly, this problem is the provision of a vaccinia virus formulation comprising a partially purified virus and having some degree of stability. The board is satisfied that this problem is solved.

Obviousness

23. It remains to be assessed whether the skilled person, when faced with the technical problem defined in point 22 above, would have modified the teaching in the closest prior art document (D14) - possibly in the light of other teachings in the prior art - so as to arrive at the claimed invention in an obvious manner.

24. It is undisputed that document (D1) discloses formulations which - except for the virus - are chemically identical to the formulation of claim 1 (see examples 4 to 6). The key question to be addressed is whether the skilled person, when embarking on finding a solution to the above problem, would have considered the teaching of document (D1).

25. The board notes that document (D1) relates to the stabilization of herpes virus preparations and thus lies in a neighbouring technical field. The compositions disclosed in document (D1) include compositions free from protein (other than any protein forming part of the active vaccine component), in particular free from gelatin or other animal protein or its hydrolysate or other material of animal origin (see column 4, lines 19 to 22, examples 4 to 6). In other words, the compositions contain purified viruses. Lyophilization of the virus containing preparations of document (D1) leads to stable compositions wherein the titer of the virus lies within 0.5 of a log of the titre found immediately after lyophilisation. Finally, document (D1) discloses that the invention, i.e. the stabilised virus formulations, are particularly applicable for herpes viruses and poxviruses (see column 6, lines 17 to 18).

26. Document (D1) thus teaches stabilised purified virus preparations that are also suitable for poxviruses. Vaccinia virus is the prototype poxvirus. In the board's judgement, the skilled person faced with the problem formulated above would therefor have been motivated to test the preparations of document (D1) on vaccinia virus.

27. As pointed out repeatedly in document (D14), the development of live vaccine formulation is empirical by nature (see e.g. page 7, lines 6 to 9 of first paragraph; line 1 of the second paragraph; page 17, third paragraph). The person skilled in the field of the development of live vaccine formulation would therefore have been aware that any formulation, and thus also the formulations disclosed in document (D1) to stabilize HSV-2, would have to be tested with vaccinia viruses to determine whether or not they also stabilize these viruses. In situations like the present, the skilled person would have either some expectation of success or, at worst, no particular expectation of any sort, but a "try and see" attitude, which does not equate with an absence of a reasonable expectation of success (see decisions T 333/97 of 5 October 2000 and T 377/95 of 24 April 2001). Accordingly, the skilled person would have arrived at a formulation comprising purified Elstree strain, dextran, sodium glutamate, sucrose, and Tris buffer (a buffer which is not a phosphate buffer), and thus at a formulation falling within the scope of claim 1, without the exercise of any inventive activity.

28. As a first line of argument, appellant I submitted that the skilled person interested in stabilising vaccinia virus would not have considered document (D1) because he or she knew that the outer membrane structure was important for the stabilisation of the virus and that the envelopes of poxviruses and herpes viruses were different. Therefore the skilled person reading document (D1) would not have applied any teaching obtained with HSV-2 to vaccinia viruses.

29. The board is not persuaded by this line of reasoning. Document (D14) consistently distinguishes between live viral vaccines which are based either on nonenveloped or on enveloped viruses (page 7, lines 1 to 3; page 8, lines 15 to 18 of last paragraph, page 17, third paragraph). A summary of stability observations of various enveloped viruses is presented in Table 3 of document (D14). Document (D14) also discloses that, in general, enveloped viruses are more labile than those lacking an envelope (page 24, third paragraph). Also document (D3) considers enveloped viruses as an entity as regards stabilisation (see page 97, left hand column, first full paragraph). In the board's judgement it can be concluded from documents (D14) and (D3) that the skilled person interested in the stabilisation of viruses distinguished mainly between enveloped and nonenveloped viruses. Herpes viruses and poxviruses are both enveloped viruses. The board is not convinced that possible differences in the size of the viruses, the chemical structure of the envelopes or the shape of the viruses would have discouraged the skilled person from transferring the formulation conditions disclosed in document (D1) for herpes viruses to a poxvirus setting. Finally, the board notes that document (D1) does not list poxviruses amidst a long, arbitrary list of viruses to which the invention is applicable. To the contrary, document (D1) specifically proposes that the invention is particularly applicable for only two classes of viruses, namely herpes viruses and poxviruses (see column 6, lines 17 to 18).

30. As a second line of argument appellant I submitted that if the skilled person had considered the teaching of document (D1), he or she would have chosen the formulation giving the best stabilisation, i.e. the formulation disclosed in example 2 of document (D1) and not the formulations of examples 4 to 6 which, while relating to partially purified viruses, provided less stabilisation.

31. The board is not persuaded by this argument either. Example 2 of document (D1) is silent as to whether the virus is purified or not. To the contrary, examples 4 to 6 relate to the stabilisation of a purified virus. The formulations of these examples stabilize the virus as can be seen from the log loss after storage of the lyophilised preparation for 25 or 40 weeks. Therefore, the skilled person, interested in providing a solution to the problem of providing a vaccinia virus formulation comprising a partially purified virus and having some degree of stability would have tested the formulations provided in examples 4 to 6 and not the formulation provided in example 2 of document (D1).

32. For these reasons the subject-matter of claim 1 is found to lack an inventive step and thus the main request is not allowable under Article 56 EPC.

Auxiliary request 2 - claim 1

Inventive step

33. Claim 1 of this request differs from claim 1 of the main request in that the formulation is more narrowly defined as further comprising glutamic acid, the disaccharide sucrose, the polymer dextran and as the vaccinia virus a MVA strain or strain Elstree. This request corresponds to the request considered allowable by the opposition division.

34. The parties agreed that document (D14) represented the closest prior art. The board sees no reason to disagree. The subject-matter of claim 1 differs from the formulation disclosed in Table 3 on page 54 of document (D14) in that it contains a partially purified virus, dextran instead of peptone, and a buffer without phosphate. Appellant I submitted that the effect of the difference was the same as for the main request and formulated the problem accordingly as the provision of a vaccinia virus formulation pure enough to allow direct administration upon reconstitution while being stable enough to prevent loss of viral titer during storage.

35. The board notes that, although in present claim 1 the components are more narrowly defined than in claim 1 of the main request, the concentrations of these components are not indicated, the virus is only partially purified, and the definition of the formulation allows for the presence of inter alia peptone, serum or animal proteins. The board is thus not satisfied that the problem as formulated by the appellant is solved across the whole scope of claim 1 (see points 19 to 22 above). Accordingly, the problem needs to be reformulated (see point 22 above) and is defined as the provision of a vaccinia virus formulation comprising a partially purified virus and having some degree of stability. The board is satisfied that this problem is solved.

36. It has been established (see points 23 to 32, above), that the skilled person faced with this problem would have combined the teaching of document (D14) with the teaching of document (D1), in particular examples 4 to 6 of document (D1), thus arriving at a formulation falling within the scope of present claim 1 in an obvious manner.

37. Appellant I submitted that the skilled person starting from the formulation disclosed in document (D14) had to get rid of peptone, and add dextran, the buffer and the viral titer in order to arrive at the claimed formulation. The sheer number of changes required spoke for the presence of an inventive step. The board notes that the presence of peptone is not excluded from the formulation of claim 1. As regards the dextran, the buffer and the viral titer, the board considers that document (D1) teaches the skilled person that it is the combination of dextran, sodium glutamate, sucrose and Tris buffer that stabilizes a purified virus (see examples 4 to 6). Therefore, the skilled person when testing the formulations disclosed in examples 4 to 6 of document (D1) with vaccinia viruses would have made all the changes required to arrive at a formulation which stabilizes the virus. Accordingly, the board is not persuaded by the argument of appellant I.

38. For these reasons the subject-matter of claim 1 is found to lack an inventive step and thus auxiliary request 2 is not allowable under Article 56 EPC.

Auxiliary requests 3 and 4

Admissibility

39. Claim 1 of auxiliary request 3 corresponds to claim 1 of auxiliary request 2, in which the option that the vaccinia virus is Elstree has been removed from the claim, thus limiting the vaccinia strain to a MVA strain. Auxiliary request 4 corresponds to auxiliary request 3 in which claim 1 has been additionally amended to specify that the buffer is TRIS. The board is satisfied that these amendments are a bona fide attempt to address the objections under inventive step, that they are straightforward and do not lead to any surprising turn of events or a fresh case. Under these circumstances the board decides to admit these requests in the proceedings in the exercise of its discretion under Article 13(1) RPBA.

Auxiliary request 3 - claim 1

Inventive step

40. This claim differs from claim 1 of auxiliary request 2 only in that the vaccinia strain is limited to a MVA strain.

41. The problem to be solved is the same as formulated above for auxiliary request 2 (see point 35 above). The board is satisfied that this problem is solved.

42. It has been established (see points 23 to 32, above), that the skilled person faced with this problem would have combined the teaching of document (D14) with the teaching of document (D1), in particular examples 4 to 6 of document (D1), thus arriving at a formulation which differs from the formulation according to claim 1 merely in that the vaccinia strain is Elstree and not MVA. It thus needs to be established whether or not the choice of the MVA strain instead of the Elstree strain can justify the acknowledgement of an inventive step. Document (D17), which can be taken to represent the common general knowledge of the skilled person at the relevant date, discloses that MVA is the "gold standard" of recombinant vaccinia viruses in clinical development (see abstract). In the board's judgement, the fact that MVA was the "gold standard" of recombinant vaccinia viruses in clinical development at the relevant date would have prompted the skilled person, when faced with the problem formulated above (see points 41 and 35), to provide a vaccinia virus formulation comprising a MVA strain. Accordingly, the board considers the choice of the MVA strain as obvious to a person skilled in the art.

43. Appellant I submitted that documents (D14), (D1) and (D17) and, thus, three documents had to be combined to arrive at the claimed solution. The board understands this as an implicit argument to the effect that the combination of more than two documents to arrive at the claimed solution indicated the presence of an inventive step. The board notes that in the present case document (D17) is merely cited to illustrate the common general knowledge of the skilled person working in the field of vaccinia viruses at the relevant date. Accordingly, two documents are combined with the common general knowledge of the skilled person. In any case, the board is not persuaded that a requirement to combine more than two documents to arrive at the claimed solution would automatically guarantee the acknowledgement of an inventive step. As pointed out above (see point 23), the relevant question to be answered is whether or not the skilled person, in the expectation of solving the problem, would have modified the teaching in the closest prior art document in the light of other teachings in the prior art so as to arrive at the claimed invention. The board is satisfied that this is the case (see point 42).

44. For these reasons the subject-matter of claim 1 is found to lack an inventive step and thus auxiliary request 3 is not allowable under Article 56 EPC.

Auxiliary request 4 - claim 1

Inventive step

45. This claim differs from claim 1 of auxiliary request 3 only in that the buffer is defined as being TRIS.

46. Since the buffer used in examples 4 to 6 of document (D1) is TRIS, no inventive step can be acknowledged for this request for the same reasons as given above for auxiliary request 3 (see points 40 to 44 above). Therefor auxiliary request 4 is not allowable under Article 56 EPC.

47. In the absence of an allowable request the patent has to be revoked.